Adipose Tissue Senescence and Inflammation in Aging is Reversed by the Young Milieu

Abstract

Visceral adipose tissue (VAT) inflammation plays a central role in longevity and multiple age-related disorders. Cellular senescence (SEN) is a fundamental aging mechanism that contributes to age-related chronic inflammation and organ dysfunction, including VAT. Recent studies using heterochronic parabiosis models strongly suggested that circulating factors in young plasma alter the aging phenotypes of old animals. Our study investigated if young plasma rescued SEN phenotypes in the VAT of aging mice. With heterochronic parabiosis model using young (3 months) and old (18 months) mice, we found significant reduction in the levels of pro-inflammatory cytokines and altered adipokine profile that are protective of SEN in the VAT of old mice. These data are indicative of protection from SEN of aging VAT by young blood circulation. Old parabionts also exhibited diminished expression of cyclin-dependent kinase inhibitors (CDKi) genes p16 (Cdkn2a) and p21 (Cdkn1a/Cip1) in the VAT. In addition, when exposed to young serum condition in an ex vivo culture system, aging adipose tissue–derived stromovascular fraction cells produced significantly lower amounts of pro-inflammatory cytokines (MCP-1 and IL-6) compared to old condition. Expressions of p16 and p21 genes were also diminished in the old stromovascular fraction cells under young serum condition. Finally, in 3T3-preadipocytes culture system, we found reduced pro-inflammatory cytokines (Mcp-1 and Il-6) and diminished expression of cyclin-dependent kinase inhibitor genes in the presence of young serum compared to old serum. In summary, this study demonstrates that young milieu is capable of protecting aging adipose tissue from SEN and thereby inflammation.

Blood Serum Stimulates p38-Mediated Proliferation and Changes in Global Gene Expression of Adult Human Cardiac Stem Cells

“…Accordingly, we could show via RNAseq that MCP1 was significantly downregulated in cells treated with young blood serum. Further, Ghosh and coworkers recently showed that levels of MCP1 in white adipose tissue in old mice were decreased upon heterochronic parabiosis with young mice and even in cell culture after conditioning with young serum [62]. In contrast to this, we detected no significant differences in the protein concentration of MCP1 between old and young plasma samples.…”

Molecular basis of ageing in chronic metabolic diseases

“…This approach can be used to test the effectiveness of intervention strategies aimed at targeting senescent cells. Indeed, both heterochronic parabiosis studies, in which young (4 months) and old (20 months) mice are surgically linked to share circulation, and ex vivo treatment of SVF cells from young and old mice with young or old serum, have shown that a young milieu is effective in protecting old AT from senescence by reducing the levels of p16, p21, and pro-inflammatory SASP factors [86].…”

“…Moreover, many effective lifespan-extending interventions act through epigenetic pathways [142]. The opportunity to "reverse" ageing is an intriguing implication of epigenetic ageing regulation, which provides a mechanistic basis for evidence that ageing hallmarks can be reversed through parabiosis experiments [86].…”

SIV Infection and the HIV Proteins Tat and Nef Induce Senescence in Adipose Tissue and Human Adipose Stem Cells, Resulting in Adipocyte Dysfunction

“…The discrepancy between p16 expression and p53 activation in VAT may be due to the fact that senescence can involve either the p53-p21 or the canonical p16-retinoblastoma protein tumor suppressor pathways [28]. We propose that in VAT the p16 pathway of senescence [29] is activated in priority by SIV and its proteins rather than that using p53. Accordingly, recent data show that aging is not associated with p53 activation in VAT [30].…”